1. Field of the Invention
This invention relates to the field of neuropsychiatry and relates specifically to methods for memory enhancement and treatment of memory deficits consequent to neurological disorders.
2. Description of the Background Art
The N-methyl-D-aspartate (NMDA) receptor, a sub-type of excitatory amino acid receptor, has been suggested to mediate learning and memory processes. Intact hippocampal structure, which has a very high density of NMDA receptors, is necessary for the brain to process information and store it in memory. Electrophysiological studies have shown that NMDA receptors are required for the induction of long-term potentiation (LTP) in the hippocampus, a phenomenon that has been proposed to underlie storage of information in the brain and to mediate certain types of memory processes. However, a causal relationship between LTP and learning and memory processes has not been unequivocally demonstrated in mammals. The NMDA receptor also has been shown to be critically involved in various types of synaptic plasticity including enhanced synaptic transmission in the visual cortex; the kindling model of epilepsy; and vestibular compensation after unilateral labyrinthectomy.
The NMDA-sensitive glutamate receptor domain includes recognition sites (1) for the primary transmitter, with which agonists (e.g., NMDA and L-glutamate) and competitive antagonists (e.g., AP5 and PCP) interact; (2) a site through which glycine and drugs acting at the strychnine-insensitive glycine receptors bidirectionally modulate ion channel function; (3) a cation-binding site inside the channel; and (4) an inhibitory phencyclidine (PCP) site located within the receptor-operated cation channel.
The function of the NMDA receptor complex can be inhibited by drugs acting through several distinct mechanisms at the various recognition sites on the ligand-gated ion channel. For example, neurophysiological studies have demonstrated that glycine potentiates the response to activation of NMDA receptors in cultured brain neurons. This is a strychnine-insensitive action and it is postulated to result from activation of a supraspinal glycine receptor which modulates the opening of the Na.sup.+ - Ca.sup.++ channel triggered by NMDA activation. The structural requirements for ligand binding to the strychnine-insensitive glycine receptors and their regional distribution in the central nervous system, with a high density in the hippocampus, have been reported to differ remarkably from strychnine-sensitive glycine receptors.
Glycine agonists are believed to facilitate NMDA transmission and to have a positive effect on cognition in certain types of learning. For example, D-cycloserine, which exhibits a good affinity for the strychnine-insensitive glycine receptor, has been shown to facilitate acquisition of a hippocampal associated learning task and has been suggested to improve cognition.
Competitive NMDA antagonists and channel blockers, like PCP and MK-801, also can affect certain types of memory and learning. For example, PCP and the use-dependent channel blocker MK-801 have been shown to interfere with the ability of mice and rats to perform in a passive avoidance test. However, other workers have demonstrated that PCP does not have a reliable effect on place learning.
To date, however, conventional methods and therapeutic agents have not proved to be effective or reliable for the improvement of cognition. For these reasons it would be desirable to provide improved methods which avoid the disadvantages of these conventional agents and methods while providing effective and reliable results.